Every year, millions of Americans receive some type of orthopaedic or dental implant. Joint prostheses (e.g. hip and knee) have been very successful in restoring function to patients, however these devices generally last only 10-15 years. Implants used for filling bone defects or lesions are even less well-developed; the current "gold standard" for treatment is autologous bone graft, which carries many associated risks and limitations. Recently, many investigators have sought to improve implant performance by modifying biomaterials with molecules that mimic the endogenous bone environment, for example, peptides derived from components of the extracellular matrix. This "biomimetics approach" has shown much promise for enhancing the bioactivity of certain types of materials, however, surprisingly, the class of materials that is among the most osseoconductive, the calcium phosphates, has received the least amount of attention in this regard. To address this deficit in biomaterials research, the broad, long-term goal of this project is to determine whether mimetic proteins/peptides, such as collagen l-derived peptides and Bone Morphogenic Protein-2 (BMP-2), can enhance the osseointegration of calcium phosphate biomaterials, particularly hydroxyapatite (HA). To accomplish this goal, we have designed 4 specific aims: Specific Aim 1: To identify biomimetic peptides that stimulate optimal in vitro human mesenchymal stem cell (MSC) attachment and differentiation. Specific Aim 2: To determine whether engineering peptides with additional domains enhances peptide tethering and/or bioactivity. More specifically, peptides will be modified by adding an HA-binding sequence, or by inserting a polylinker domain between the HA- and cell-binding motifs. Specific Aim 3: To test the efficacy of peptide coatings in promoting adhesion and differentiation of endogenous MSCs, leading to enhanced bone formation. A rat tibial implantation model will be used to test peptide efficacy in vivo. Specific Aim 4: To determine whether osseointegration can be improved by pre-loading scaffolds with MSCs. Public-health relatedness: The major goal of this study is to optimize the performance of calcium phosphate biomaterials that are commonly used for joint prosthetic and bone replacement applications.